How a Love of "Story Problems" Changed the World of Breast Cancer

A series of graduate student conversations with leading women biologists, at the Women in Science Symposium at Cornell April 2-3.

“If all the people for whom nothing ever worked dropped out of science, there'd be nobody left.” These were the words that convinced Dr. Mary-Claire King to remain in graduate school many years ago. And it’s a good thing she did – Dr. King has since made significant contributions to the field of human genetics. Among her many accomplishments, she showed that humans and chimpanzees are 99% similar at the DNA sequence level, discovered genes responsible for heritable breast and ovarian cancer, and applied genetic technologies to help solve human rights cases. Today, Dr. King’s lab at the University of Washington continues to push the boundaries of these fields.

Last week, I had the opportunity to talk with Dr. King about her career path and her research on breast cancer during the Frontiers Symposium at Cornell University. While her road to success was not easy, three valuable lessons emerge from it: (1) Follow your passion even if it requires starting over, (2) learn to recognize and work around your limits, and (3) never, ever give up.

Lesson 1: Follow your passion

What inspired Dr. King to begin a career in human genetics? Baseball. Well, technically, math problems about baseball. Dr. King grew up watching baseball games with her father, who would create story problems about the batting averages, fielding percentages, and pitching stats of the Cubs and the White Sox. She loved working through the puzzles posed by her father. This early interest in problem solving led her to pursue mathematics as an undergraduate at Carleton College and to start a Ph.D. in statistics at UC Berkeley.

Dr. King “realized very early on that [she] wasn't good enough at math to really do theoretical mathematics or statistics well.” In addition, she wanted to do something more applied. She enrolled in Dr. Curt Stern’s genetics class at Berkeley and found her true passion.

“I thought, I can't imagine getting paid to do this,” said Dr. King. “This is nothing but story problems. One story problem after another…this is terrific!”

Lesson 2: Recognize and work around your weaknesses

Dr. King transferred to genetics, and “then it was a very long slog.” She had never done experimental biology before, and she admits that she wasn’t very good at labwork. Her frustrations in the lab were compounded by the political environment at the time: it was the late 1960s, and Dr. King was an active participant in the anti-Vietnam war movement. She worked for a year with Ralph Nader, and when he offered her a job in Washington, D.C., she considered dropping out of graduate school.

While debating whether to stay in school, Dr. King consulted her mentor and eventual Ph.D. advisor Dr. Allan Wilson, who convinced her to stay in science. Failures were a matter of course in science, he argued, and a Ph.D. would grant her more autonomy in the future, regardless of what she chose to do. He worked with her to identify an interesting project that didn’t require a lot of laboratory prowess but had a strong analytic component. The two of them went on to write one of the classic papers of molecular evolution. They used protein electrophoresis to demonstrate the high degree of similarity between humans and chimps, and suggested that the substantial anatomical and behavioral differences between the two species were due to regulatory mutations.

Dr. King’s Ph.D. thesis created a furor in the scientific community at the time but has since reached far beyond the field of evolutionary biology. When traveling around Ireland with her then-teenage daughter, Dr. King saw a billboard reading: “Scientists have shown humans and chimps share 99% of their genes. Drink Guinness.” That billboard prompted her uncharacteristically impressed daughter to blurt out, “That’s you, Mom!”

Lesson 3: Never give up

After getting her Ph.D., Dr. King moved to Chile for a few years before completing postdoctoral work at UCSF and accepting a faculty position at UC Berkeley. She decided to tackle a new problem: why is breast cancer familial? Dr. King suspected that genetics might play a role. To test her hypothesis, all she had to do was to find the gene or genes involved. Simple to say, but not so simple to do.

This was during the early days of developing a genetic understanding of diseases that follow the principles of Mendelian inheritance (e.g., cystic fibrosis and Huntington’s disease). Few believed there could be a simple genetic basis for a heritable predisposition to complex diseases such as breast and ovarian cancer.

When I asked if she was ever scared that breast cancer wasn’t genetic and that she was searching for nothing, Dr. King replied, “Of course I thought many, many, many times that this was a completely nonsensical hypothesis.” But that didn’t stop her from trying.

This may be counterintuitive, but being one of the few women in science at the time actually helped. “We had a good fraction of the women in science from that era here today [at the Frontiers Symposium at Cornell],” she joked. “It was a small field.” Instead of being frustrated that nobody cared about her work, Dr. King found it liberating to be able to operate under the radar. “No expectations led to freedom to think in unconventional ways,” she said. She obtained small grants from the National Cancer Institute and focused on her research.

Dr. King was once again working on a story problem, only instead of comparing the batting averages of two baseball teams, she was evaluating the family histories reported by 1500 women with breast cancer. She built a mathematical model that provided clear statistical evidence for a gene that drives risk of breast cancer. But to validate the predictions of the model, she still had to physically locate the gene.

So Dr. King and her lab started genetic mapping. The goal: to identify and locate the gene(s) responsible for inherited risk of breast cancer and to develop clinical applications useful to as many women as possible, as soon as possible. She received a lot of help from surgeons who referred families severely affected by breast cancer to her. In 1990, she identified a locus responsible for breast cancer in families with early onset disease. She named the gene breast cancer 1, or BRCA1.

That discovery changed the worlds of breast cancer oncology and cancer research. To date, scientists have identified 21 genes that carry inherited mutations that significantly increase the risk of breast or ovarian cancer.

Solving the problem of breast cancer

Currently, Dr. King is working on the ultimate story problem in breast cancer research: now that we have an understanding of the genetic and environmental risk factors for these cancers, how can we eliminate inherited breast and ovarian cancer?

The King lab has developed an inexpensive, “one-stop” test that fully screens all genes known to increase risk of breast and ovarian cancer. Their approach will remain unpatented to increase access, and they are collaborating with clinical laboratories worldwide to set up the screening procedure. Knowledge about these mutations is critical for both prescribing effective treatment plans for existing tumors and suggesting preventative measures in as-yet cancer-free patients. In certain communities, where screening for BRCA1 and BRCA2 mutations is widespread, rates of ovarian cancer are beginning to drop.

Dr. King would like every woman to be offered genomic screening for inherited risk of breast and ovarian cancer at about age 35. The costs of such testing are substantial, but far less than the costs – both in dollars and in suffering – of treating cancers after they occur. She believes in the potential of genomic medicine and remains optimistic that this dream may eventually become reality.

“It’s a promise we need to keep,” she said near the end of our conversation.

The views expressed are those of the author(s) and are not necessarily those of Scientific American.

ABOUT THE AUTHOR(S)

Nancy Chen

Nancy Chen received an A.B. in Biochemical Sciences from Harvard University then switched fields after becoming fascinated with evolution and genetics. Now she is a graduate student in Ecology and Evolutionary Biology at Cornell University and the Cornell Lab of Ornithology, where she studies evolutionary genetics of endangered birds. Nancy's interest in birds is both professional and recreational: when not wading through mountains of DNA sequence data, she loves birding, hiking, and cooking with friends. For more on her research, visit her website.

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